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Deterministic progenitor behavior and unitary production of neurons in the neocortex.

Gao P, Postiglione MP, Krieger TG, Hernandez L, Wang C, Han Z, Streicher C, Papusheva E, Insolera R, Chugh K, Kodish O, Huang K, Simons BD, Luo L, Hippenmeyer S, Shi SH - Cell (2014)

Bottom Line: We found that RGPs progress through a coherent program in which their proliferative potential diminishes in a predictable manner.Removal of OTX1, a transcription factor transiently expressed in RGPs, results in both deep- and superficial-layer neuron loss and a reduction in neuronal unit size.These results suggest that progenitor behavior and histogenesis in the mammalian neocortex conform to a remarkably orderly and deterministic program.

View Article: PubMed Central - PubMed

Affiliation: Developmental Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Graduate Program in Neuroscience, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.

ABSTRACT
Radial glial progenitors (RGPs) are responsible for producing nearly all neocortical neurons. To gain insight into the patterns of RGP division and neuron production, we quantitatively analyzed excitatory neuron genesis in the mouse neocortex using Mosaic Analysis with Double Markers, which provides single-cell resolution of progenitor division patterns and potential in vivo. We found that RGPs progress through a coherent program in which their proliferative potential diminishes in a predictable manner. Upon entry into the neurogenic phase, individual RGPs produce ?8-9 neurons distributed in both deep and superficial layers, indicating a unitary output in neuronal production. Removal of OTX1, a transcription factor transiently expressed in RGPs, results in both deep- and superficial-layer neuron loss and a reduction in neuronal unit size. Moreover, ?1/6 of neurogenic RGPs proceed to produce glia. These results suggest that progenitor behavior and histogenesis in the mammalian neocortex conform to a remarkably orderly and deterministic program.

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Outline of MADM-Based Clonal Analysis of Neocortical Excitatory Neuron Production and Organization, Related to Figure 1(A) Schematic of MADM labeling.(B) Experimental paradigm of MADM-based clonal analysis. A single dose of TM treatment is performed at E10, E11, E12 or E13, and brains are analyzed at P7-10, when neuronal migration in the neocortex is mostly finished, or P21-30, when neocortical development is largely complete.
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figs1: Outline of MADM-Based Clonal Analysis of Neocortical Excitatory Neuron Production and Organization, Related to Figure 1(A) Schematic of MADM labeling.(B) Experimental paradigm of MADM-based clonal analysis. A single dose of TM treatment is performed at E10, E11, E12 or E13, and brains are analyzed at P7-10, when neuronal migration in the neocortex is mostly finished, or P21-30, when neocortical development is largely complete.

Mentions: In MADM, Cre recombinase-mediated interchromosomal recombination in the G2 phase of dividing progenitors followed by X-segregation (G2-X, segregation of recombinant sister chromatids into separate daughter cells) reconstitutes one of two fluorescent markers, enhanced GFP (EGFP, green) or tandem dimer Tomato (tdTomato, red), in each of the two daughter cells (Figure S1A available online) (Zong et al., 2005). As such, G2-X MADM events result in permanent and distinct labeling of the two descendent lineages, thereby allowing a direct assessment of the division pattern (symmetric versus asymmetric) and potential (the number of progeny) of the original dividing progenitors. In addition, upon G2-Z (congregation of recombinant sister chromatids into the same daughter cell), G1, or G0 recombination events, green and red fluorescent proteins are restored simultaneously in the same cell, resulting in double-labeled (yellow) cells (Figure S1A).


Deterministic progenitor behavior and unitary production of neurons in the neocortex.

Gao P, Postiglione MP, Krieger TG, Hernandez L, Wang C, Han Z, Streicher C, Papusheva E, Insolera R, Chugh K, Kodish O, Huang K, Simons BD, Luo L, Hippenmeyer S, Shi SH - Cell (2014)

Outline of MADM-Based Clonal Analysis of Neocortical Excitatory Neuron Production and Organization, Related to Figure 1(A) Schematic of MADM labeling.(B) Experimental paradigm of MADM-based clonal analysis. A single dose of TM treatment is performed at E10, E11, E12 or E13, and brains are analyzed at P7-10, when neuronal migration in the neocortex is mostly finished, or P21-30, when neocortical development is largely complete.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4225456&req=5

figs1: Outline of MADM-Based Clonal Analysis of Neocortical Excitatory Neuron Production and Organization, Related to Figure 1(A) Schematic of MADM labeling.(B) Experimental paradigm of MADM-based clonal analysis. A single dose of TM treatment is performed at E10, E11, E12 or E13, and brains are analyzed at P7-10, when neuronal migration in the neocortex is mostly finished, or P21-30, when neocortical development is largely complete.
Mentions: In MADM, Cre recombinase-mediated interchromosomal recombination in the G2 phase of dividing progenitors followed by X-segregation (G2-X, segregation of recombinant sister chromatids into separate daughter cells) reconstitutes one of two fluorescent markers, enhanced GFP (EGFP, green) or tandem dimer Tomato (tdTomato, red), in each of the two daughter cells (Figure S1A available online) (Zong et al., 2005). As such, G2-X MADM events result in permanent and distinct labeling of the two descendent lineages, thereby allowing a direct assessment of the division pattern (symmetric versus asymmetric) and potential (the number of progeny) of the original dividing progenitors. In addition, upon G2-Z (congregation of recombinant sister chromatids into the same daughter cell), G1, or G0 recombination events, green and red fluorescent proteins are restored simultaneously in the same cell, resulting in double-labeled (yellow) cells (Figure S1A).

Bottom Line: We found that RGPs progress through a coherent program in which their proliferative potential diminishes in a predictable manner.Removal of OTX1, a transcription factor transiently expressed in RGPs, results in both deep- and superficial-layer neuron loss and a reduction in neuronal unit size.These results suggest that progenitor behavior and histogenesis in the mammalian neocortex conform to a remarkably orderly and deterministic program.

View Article: PubMed Central - PubMed

Affiliation: Developmental Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Graduate Program in Neuroscience, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.

ABSTRACT
Radial glial progenitors (RGPs) are responsible for producing nearly all neocortical neurons. To gain insight into the patterns of RGP division and neuron production, we quantitatively analyzed excitatory neuron genesis in the mouse neocortex using Mosaic Analysis with Double Markers, which provides single-cell resolution of progenitor division patterns and potential in vivo. We found that RGPs progress through a coherent program in which their proliferative potential diminishes in a predictable manner. Upon entry into the neurogenic phase, individual RGPs produce ?8-9 neurons distributed in both deep and superficial layers, indicating a unitary output in neuronal production. Removal of OTX1, a transcription factor transiently expressed in RGPs, results in both deep- and superficial-layer neuron loss and a reduction in neuronal unit size. Moreover, ?1/6 of neurogenic RGPs proceed to produce glia. These results suggest that progenitor behavior and histogenesis in the mammalian neocortex conform to a remarkably orderly and deterministic program.

Show MeSH